The chemical name of pemetrexed disodium is N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid disodium salt, represented by the following formula:

Pemetrexed disodium is an anti-tumor medicament against folic acid metabolism, which functions by interfering with folic acid-dependent metabolism process in the cell replication. As in vitro experiment demonstrates, pemetrexed disodium can inhibit folic acid-dependent enzymes, such as thymidylate synthetase, dihydrofolate reductase and glycineribonucleosideformyltransferase, which involve the biosynthesis of thymidine and purine nucleoside.
Currently, the commonly used process for preparing pemetrexed disodium is disclosed in EP 0905128. In the process disclosed, 4-(4-carbomethoxyphenyl)butanal is a key intermediate for preparing pemetrexed disodium.
Three processes for preparing 4-(4-carbomethoxyphenyl)butanal have been reported:
1. J. Org. Chem., 1990, 55:3222-7 has reported that the intermediate can be obtained by condensing 3-butyn-1-ol with methyl p-bromobenzoate, hydrogenating with palladium carbon (Pd/C), and oxidizing the resulting alcohol by PCC. Such process is tedious and some reagents are expensive.
2. Tetrahedron Letters, 1989, 30:6629-32 has reported that the intermediate can be obtained by condensing 3-buten-1-ol with methyl p-bromobenzoate, and separating by column chromatography to obtain a pure product. Such process is not suitable for industrial production due to the use of column chromatography.
3. Chemical Industry Times, 2006, 20:54-55 has reported that the intermediate can be obtained by reacting the crude product of 4-(4-carbomethoxyphenyl)butanal obtained by condensing 3-buten-1-ol and methyl p-bromobenzoate with sodium bisulfite to provide a sulfonate salt, then treating the sulfonate salt with hydrochloric acid to produce a pure intermediate. The product obtained by such process is of high purity, however, the total yield is merely 38%.
Therefore, there is an urgent need in the art for improving the process for preparing 4-(4-carbomethoxyphenyl)butanal in order to prepare pemetrexed disodium more efficiently, and in a industrial-scale.